Project Description The high probability of breakdown in the functioning of the central nervous system (CNS) during late stages of aging, as in Alzheimer?s disease and various dementias is a major concern for the elderly. Triggers that initiate age-associated diseases and neurological conditions are for the most part unknown. A key to these associations could be the population of ependymal cells in the brain. Ependymal cells form a monolayer that functions as a barrier between the cerebrospinal fluid (CSF) and the overlying cellular compartments of the brain. As such, they regulate CSF production, circulation, and filtering, and thus ependymal cells are a key component of the newly described ?glymphtic-lymphatic? system. This system is purported to control CSF- vascular interactions in the brain parenchyma and thus contribute to the overall clearance of the brain of toxicants and metabolic byproducts and allow entry of immune cells into the brain. The ependymal layer appears damaged in the aged brain, yet whether the damage is caused by malfunctioning signals in the overlying CNS tissue, or if ependymal damage causes defects in neurons and glia in the CNS remain unknown. We have developed several genetic mouse models which suggest the ependymal layer may be the root of many problems in the brain interstitium related to various neurodegenerative diseases and during normal aging in the CNS. We will use these models to study this novel concept. Studies in our mouse models have revealed a previously unknown expression and clearance of mucins by ependymal cells in the CNS. Since mucins function to protect against inflammation and infectious diseases in other tissues, our results have led to the central hypothesis that mucin secretion by ependymal cells is required for maintenance and functional integrity of homeostasis in the forebrain during aging, and that disruption of mucin secretion can lead to aberrant function and disease in the CNS. Our project uses a variety of genetic mice, together with cellular, molecular, and biochemical approaches to test our hypothesis. Potential for Broader Impact: Our approaches to understand how aging affects the brain through its monolayer of ependymal cells have wide implications. Disruption of filtration and protective functions of ependymal cells may be the root of a range of pathological conditions that emerge during late stages of aging. Therefore, undertaking the basic cellular mechanisms that control aging of the brain is critical to understanding not only how healthy aging may be controlled by ependymal cells, but also how abnormalities in ependymal aging may lead to devastating diseases such as Alzheimer?s. Moreover, the mechanisms we study can be harnessed to develop novel aging therapeutics by targeting ependymal functions selectively.